Substituted - 17alpha - buta - 1&#39;,3&#39;-diynyl-17beta-hydroxy(17beta-alkoxy)-steroids and process for preparation thereof



3,463,797 SUBSTITUTED 17oz BUTA 1',3'-DIYNYL-17fl-HY-DROXY(17fi-ALKOXY)-STEROIDS AND PROCESS FOR PREPARATION THEREOF PeterFeather and Vladimir Petrow, London, England, assignors to The BritishDrug House Limited No Drawing. Filed Jan. 27, 1967, Ser. No. 612,081Claims priority, application great Britain, Feb. 3, 1966,

66 Int. Cl. C07c 169/ 08, 169/20; A61k 17/00 US. Cl. 260-3974 22 ClaimsABSTRACT OF THE DISCLOSURE This invention is for improvements in orrelating to organic compounds and has particular reference to 17u-butal,3 diynyl 1713 hydroxy(17fl alkoxy) steroids in which theterminal hydrogen atom of the butadiynyl group has been replaced by analkyl, hydroxyalkyl, alkenyl, alkynyl or aryl group, and to a processfor their preparation.

In our copending application Ser. No. 559,731 filed June 23, 1966 isdescribed a process for the preparation of the hitherto unreported 17aalka 1',3 diynyl 17B hydroxy(l7fi-alkoxy)-steroids, which processcomprises the direct alkylation of the corresponding 17ot-butal,3-diynylsteroids, and in our copending application Ser. No. 576,866 filed Sept.2, 1966 is described an improved process for the preparation ofl7u-alka-1,3-diynyl'17B-hydroxy(17,8-alkoxy)-steroids which processcomprises reacting the corresponding 17-oxosteroids with a metallicderivative of the appropriate alka-l,3-diyne.

17a alka 1',3 diynyl 17,8 hydroxy(17/3 alkoxy)- steroids and thecompounds of the present invention are of value in the art on account oftheir potent hormonal and anti-hormonal properties, includingoestrogenic, progestational, claudogenic, ovulation-inhibiting andgonadotrophin-inhibiting properties. Additionally, some of them willhave an efliect upon cervical mucus. Thus, the compounds are of value inpreparations for the treatment of a wide range of conditions and defectsof the reproductive system and for the limitation or enhancement offertility both in the veterinary and human fields. Some of the compoundsmay have lipotrophic properties, or effects on the reticulo-endothelialsystem, rendering them of value in such fields, for example, as thetreatment of circulatory disorders and the enhancement of resistance toinfection. The compounds may be administered in the forms of tablets,pills, injections, vaginal tampons and other standard pharmaceutical andveterinary preparations.

It is an object of the present invention to provide certain newsubstituted 17a buta 1',3' diynyl 17B- hydroxy(l7fl-alkoXy)-steroidshaving the partial Formula I below where R is H or an alkyl groupcontaining not more than 5 carbon atoms; and R is an alkyl, hydroxyalkylor alkenyl group containing not more than 5 carbon atoms, or an alkynylgroup containing not more than 7 carbon atoms, or an aryl groupcontaining not more than 9 carbon atoms.

United States Patent 0 3,463,797 Patented Aug. 26, 1969 The inventionprovides hydroxyalkyl-, 17aalkenyl-, l7a-alkynylandl7a-aryl-buta-l,3-diynyl-17 8 hydroxy(17fl-alkoxy)-steroids having thepartial formula Where R is H or an alkyl group containing not more than5 carbon atoms and R is a hydroxyalkyl or alkenyl group containing notmore than .5 carbon atoms or an alkynyl group containing not more than 7carbon atoms or a aryl group cotaining not more than 9 carbon atoms.

The invention also provides the following specific substituted 17a butal',3' diynyl 17p hydroxy(17fl alkoxy steroids 17a-(5-hydroxy-penta-1,3-diynyl) -3,l7;i-dimethoxyoestral,3,5 l0) -triene 17a-(4'phenyl-buta-1',3'-diynyl) -3,17,8-dimethoxyoestra-1,3,5(10)-trienewhich has oestrogenic activity in the mouse17a-heX-5'-enl',3'-diynyl-3-methoXy-oestra-1,3,5, 10)- trien-17,B-olwhich has claudogenic activity in ratsl7ot-n-octa-l',3-diynyl-androst-5-en-3,l7fl-diol 17a-octal ',3',5'triynyl-3,17,B-dimethoXy-oestra- 1,3,5 l0)-triene which hasclaudogenic activity in rats17a-hepta-1',3',5-triynyl-B-methoxy-oestra-1,3,5 l0)- trien-17B-ol whichhas oestrogenic activity in the mouse17oc-octa-1,3',diynyl-oestra-1,3,5(10)-triene-3,l7p-diol 17fi-hYdIOXY-6ot-Il'l6thY1- 17 u-octa-l',3'-diynyl-androst-4- en-3-one3-diethylaminoethoxy-17a-octa-1',3-diynyl-oestra- 1,3,510)-trien-17,6'-olRac-17tx-(hexa-1',3'-diynyl)-3-methoxy-l8-methyloestra- 1,3,5l0)-trien-l7fl-ol 17u-phenylbutadiynyl-androst-S-ene-3B,17,3-diol.

According to the present invention there is provided a new process forthe preparation of substituted l7a-buta-1',3-diynyl-17fi-hydroxy(17fi-alkoXy)-steroids having the partialformula where R is H or an alkyl group containing not more than 5 carbonatoms; and R is an alkyl, hydroxyalkyl or alkenyl group containing notmore than 5 carbon ators, or an alkynyl group containing not more than 7carbon atoms, or an aryl group containing not more than 9 carbon atoms,which process comprises treating an ethylnyl compound R"CESH with acuprous salt and a bromoethynyl compound R"'-C*=-CBr where one of R andR'" represents a steroidal moiety with the ethynyl or bromoethynyl groupattached at C and the other of R" and R represents an alkyl,hydroxyalkyl or alkenyl group containing not more than 5 carbon atoms,or an alkynyl group containing not more than 7 carbon atoms, or an arylgroup containing not more than 9 carbon atoms.

The cuprous salt is preferably cuprous chloride. The reaction whichresults in the formation of the required buta-1,3'-diynyl chain may berepresented as follows:

where R" and R' have the same meaning as above.

Advantageously, the process of the invention may be carried outemploying a catalytic quantity of cuprous chloride. Of the two reagentsR"CECH and the non-steroidal reagent is preferably present in a small ormoderate excess. It is desirable to carry out the reaction in thepresence of a base, such as ethylamine, to take up hydrogen halide andof a reducing agent, preferably a salt of hydroxylamine, to maintain thecopper in the cuprous state. The process of the invention may be carriedout under an inert atmosphere at temperatures between 10 C. and 40 C. orhigher, or advantageously at C. or room temperature. The reactiongenerally takes place rapidly but times up to 2 hours are convenientlyallowed to ensure completion. A Wide range of organic solvents issuitable for the reaction providing that the cuprous salt of the ethynylcompound is adequately soluble, but polar solvents, and especiallymixtures consisting of an alcohol and N,N-dimethylformamide containingsome water, are preferred. When reaction is complete, a reagent, forexample potassium cyanide, may be added to destroy any residualacetylenic cuprous compound, and the steroidal product may be recoveredaccording to the usual procedures of the art, for example by dilutingthe mixture with water and filtering or extracting with a solvent suchas ether, with subsequent purification by chromatography and/orcrystallisation from a suitable solvent.

With a suitable choice of reaction conditions the requiredsubstituted-17a buta-1',3-diynyl-l7fi-hydroxy (|17;8-alkoxy)-steroid isobtained in favorable yield. The process of the invention is rapid,simple to perform, and avoids handling some of the hazardous reagentsrequired by our earlier processes, such as liquid ammonia,alkal,3-diynes, 1,4-dichloro-but-2-yne (a powerful vesicant) and itshomologues. Numerous ethynyl and bromoethynyl components are readilyavailable or may conveniently be prepared by well-konwn procedures, sothat the process of the invention is particularly suitable for thepreparation of a wide range of substituted-17ot-buta-1,3'-diynyl-steroids.

It will be apparent to those skilled in the art that the process of theinvention may be applied to steroids containing the wide variety ofstandard steroidal substituents and unsaturated linkages in Rings A, B,C and D.

It is, in general, desirable to protect carbonyl groups, and inparticular carbonyl groups at C C C C C and C from attack during thecourse of the reaction. Such protection may be achieved, for example, byprior conversion into a ketal, thioketal, enamine or enol ether, andsubsequent regeneration. However, it may be found in practice thatnegligible attack on the carbonyl group occurs in the short timerequired for the process of the invention and a satisfactory product maybe obtained without protecting the carbonyl group.

Hydroxy groups and in particular hydroxy groups at C1 2 C3! C4 C5! 6 C7:C9, C11: C12: C14: C15: C16 and C are not disadvantageous and may incertain cases, particularly in instances in which the ethynyl groupinvolved in the process of the invention is attached to the steroidalnucleus, lead to an increased yield of the desired product.

Alkoxy groups, including diaminoalkoxy groups, at such positions as C CC and C do not impede the process of the invention and do not suiferattack.

Alkyl and alkenyl groups containing up to 3 carbon atoms and inparticular methyl or methylene groups at C C C C C C and C do not, ingeneral, interfere with the process of the invention.

Unsaturated linkages, and in particular such linkages at 1 2 3 4, 5,5(10) 6 7 8: rum 9, 9(l1): 11 and A and combination of such unsaturatedlinkages including aromatic Rings A and/or B do not, in general,interfere with the process of the invention.

New steroids provided by the present invention may belong to theandrostane, 19-norandrostane, oestrane, 18-

methyl-oestrane, 18-ethyloestrane, oestratriene, IS-methyl-oestratrieneor l8-ethyl-oestratriene series or stereoisomers thereof and mayoptionally contain unsaturated linkages at A1: A2 A3! A4, A52 A500)! A6!A7: A8: A9: A9(11): A or A or combinations of two or more suchunsaturated linkages including aromatic Rings A and/or B1 y y groups at1, 2 3, 4 5, 6, 7 11, C and C or derived acyloxy groups containing notmore than 5 carbons atoms, or combinations of two or more such groups:3-dialkylaminoalkoxy groups in which the alkyl groups may contain up to5 carbon atoms; alkoxy groups containing not more than 5 carbon atoms atC C alkyl or alkenyl groups containing up to 3 carbon atoms at C C C C Cor C or combinations of two or more such groups; carbonyl groups at C CC C or C or combinations of two or more such groups.

It will be understood that the process of the invention may be carriedout with any 17a-ethynyl or 17a-bromoethynyl steroid compounds havingany known combination of substituents and unsaturated positions as setforth above.

Following is a description by way of example of methods of carrying theinvention into effect.

EXAMPLE 1 (\Me CEC-CECCH3 Propyne (3 g.) in N,N-dimethyl-formamide (25ml.) was added to a stirred mixture of cuprous chloride (0.2 g.),hydroxylamine hydrochloride (0.36 g.), methanol (25 ml.),N,N-dimethyl-formamide (40 m1.) and aqueous ethylamine (5.2 ml.; 70%under nitrogen, followed, after 5 minutes by17a-bromoethynyl-3-methoxy-oestra- 1,3,5 lO)-trien-17fiol (2.0 g.) inN,N-dimethyl-formamide (20 ml.). The mixture was stirred for 1 /2 hoursat room temperature, treated with potassium cyanide (0.4 g.) in water (5ml.) and poured into water. The precipitate was collected and stirredwith methanol, the portion insoluble in methanol being rejected. Theresidue from evaporation of the methanol was purified by chromatographyon alumina (50 g.), eluting with toluene, which afforded17u-penta-1',3'-diynyl 3 methoxy-oestra-1,3,5 (10)-trien-17fl-ol, [a] 50(c. 0.998 in dioxan);

xEtOH 279 my. (6, 2030 287 my (6, 1940 g; 3607,

1113K. 2240, 1609, 1592 @m. 2,9,2; 1253, 1043 cm.

EXAMPLE 2 17 a-penta- 1 ',3 '-diynyl-3,17p-dimethoxy-oestra- 1,3,5(10)-triene OMo Me I MeO- A 220 m (6, 8850), 278 m (e, 2040), 286 mu (6,

max.

EXAMPLE 3 17 (5'-hydroxy-penta-1,3 -diyny1)-3,17p-dimethoxyoestra-1,3,5()-triene OMe Me YC C--CECCH1OH MeO Propargyl alcohol (0.5 g.) was addedto a stirred mixture of cuprous chloride (0.05 g.), hydroxylaminehydrochloride (0.09 g.), methanol (6.5 ml.) N,N-dimethyl-formamide (10ml.) and aqueous ethylamine (1.3 ml.: 70% under nitrogen at 0 C.followed, after 2 minutes by 17a-bromoethynyl-3,17,8-dimethoxy-oestra-L3,5 10 triene (1.0 g.) in N,N-dimethyl-formamide (10 ml.). The mixturewas stirred for 2 minutes at 0 C., treated with potassium cyanide (0.1g.) in water (10 ml.) and diluted with water ml.). The precipitate wascollected and purified by thin-layer chromatography on silica gelimpregnated with silver nitrate, eluting with toluene/ ethyl acetate,and afforded 17a-(5-hydroxy-penta-1,3'- diynyl)-3,17B-dimethoxy-oestra1,3,5(10) triene, A 278M (s, 2020), 287 m (e, 1940);

W 3596, 2240, 1608 cm.- CS2 max. 'max.

042 omf17a-(4-phenyl-buta-1',3-diynyl)-3,17/3-dimethoxyoestra-1,3,5(10)-trieneOMe ---CEo cEc- 0Q MeO (A) Phenyl-acetylene (0.5 g.) (T. H. Vaughn, R.R. Vogt and I. A. Nieuwland, J. Am. Chem. Soc., 1934, 56, 2121) wasadded to a stirred mixture of cuprous chloride (0.05 g.), hydroxylaminehydrochloride (0.09 g.), methanol (6.5 ml.), N,N-dimethyl-formamide (10m1.) and aqueous ethylamine (1.3 ml.: 70%), under nitrogen at 0 C.,followed after 2 minutes by 17ot-bromoethyny1-3,l7fi-dimethoxy-oestra-1,3,5(10)triene (1.0 g.) in N,N-dimethyl-formamide 10 ml.). The mixture was stirred for 2 minutes at 0C., treated with potassium cyanide (0.1 g.) in water (10 ml.) anddiluted with water (20 ml.). The precipitate was collected and purifiedby thinlayer chromatography on silica gel impregnated with silvernitrate, eluting with toluene and by crystallisation from aqueousmethanol, affording 17a-(4'-phenyl-buta- 61',3'-diynyl)-3,17fl-dimethoxy-oestra 1,3,5(10) triene, M.P. 106 C., [u]8O (c. 0.87 in diOXan);

x333 225 my (6, 64500), 246 m (e, 3920), 259 m (E, 20200), 274 m (5,33100 290 m (e, 20700); x519 221.5 D111 (6, 4.3300 303 m,. (e, 24.00

(B) 3,l7fi-dimethoxy 17 ethyny1-oestra1,3,5 (l0)- triene (German Patent1,062,698) (1.0 g.) in N,N-dimethyl-formamide (10 ml.) was added to astirred mixture of cuprous chloride (0.20 g.), hydroxylaminehydrochloride (036 g.), methanol (26 ml.), N,N-dimethylformamide (40ml.) and aqueous ethylamine (5.2 ml.: 70%), under nitrogen at 0 C.,followed, after 15 minutes by 1-bromo-Z-phenyl-acetylene (8 g.) (F.Straus, L. Kollek and W. Heyn, Ben, 1930, 63, 1868). The mixture wasstirred at 0 C. for 30 minutes, treated with potassium cyanide (0.4 g.)in water (40 ml.) and diluted with water to precipitate the product. Thesolid was collected and purified by thin-layer chromatography on silicagel impregnated with silver nitrate, eluting with toluene, and bycrystallisation from aqueous methanol, affording c-(4-pheny1-buta-1',3-diynyl) 3,17,18 dimethoxy-oestra-l, 3,5(10)-trieneidentical with the product reported in (A) above.

EXAMPLE 5 17a-hex-5'-en-1',3-diynyl-3-methoxy-oestra- 1,3,510)-trien-17B-oll Vinyl-acetylene (0.5 g.) in N,N-dimethyl-formamide (10ml.) was added to a stirred mixture of cuprous chloride (0.10 g.),hydroxylamine hydrochloride (0.18 g.), methanol (13 ml.),N,N-dimethyl-formamide (20 ml.) and aqueous ethylamine (2.6 ml.: 70%),under nitrogen at 0 C. followed, after 2 minutes, by 17a-bromoethynyl-3-methoxy-oestra-1,3,5(10)-trien-17,8-ol (2.0 g.) in N,N-dimethyl-formamide (20 ml.). The mixture was stirred at 0 C. for 5minutes, treated with potassium cyanide (0.2 g.) in water (20 ml.) anddiluted with water (50 ml.). The steroidal product was recovered byextraction with ether. The etheral solution was dried (Na SO andevaporated at reduced pressure, and the residue, purified by thin-layerchromatography on silica gel impregnated with silver nitrate, elutingwith toluene/ethyl acetate, afforded 17a-hex-5'-en-1',3'-diyny1 3methoxy oestra- 1,3,5(10)-trien-17/3-ol,

MeO-

EXAMPLE 6 17u-n-octa-1,3 -diynyl-androst-5-en-3,17/3-diol17a-ethynyl-androst-5-en-3,1713-diol (2.0 g.) in N,N- dimethyl-formamide(30 ml.) was added to a stirred mixture of cuprous chloride (0.20 g.),hydroxylamine hydrochloride (0.36 g.), methanol (13 ml.),N,N-dimethylforrnamide (20 ml.) and aqueous ethylamine (2.6 ml.: 70%)under nitrogen at room temperature, followed, after 15 minutes byl-bromo-n-hex-l-yne (1.98 g.) in N,N-dimethyl-formamide ml.). Themixture became blue and further hydroxylamine hydrochloride (1 g.) wasadded to decolourise it. The mixture was stirred at room temperature for1% hours, treated with potassium cyanide (0.2 g.) in water ml.) andpoured into water (1 litre). The precipitate was collected and purifiedby thin-layer chromatography on silica gel impregnated with silvernitrate, eluting with ethyl acetate, afiording17a-nocta-1',3-diynyl-androst-5-en-3,17l8-di0l, M.P. 181 C.,

[01],; -144.5 (c. 0.89 in dioxan);

A222? 230 my. (6, 348), 242 m (e, 354), 256 my (6, 213) EXAMPLE 717a-n-octa-1',3'-diynyl-3-methoxy-oestra- 1,3,5( 10) -trien-17/i-ol OHMe p j ogo-ozo-oim 17u-ethynyl-3-methoxy-oestra-1,3,5(10)-trien 17,8 01(1.0 g.) in N,N-dimethyl-formamide (15 ml.) was added to a stirredmixture of cuprous chloride (0.05 g.), hydroxylamine hydrochloride (0.09g.), methanol (6.5 ml.), N,N-dimethyl-formamide 10 ml.) and aqueousethylamine (1.3 ml.: 70%) under nitrogen at room temperature, followed,after 3 minutes by l-bromo-n-hex-l-yne 1.0 g.) in N,N-dimethyl-formamide(5 ml.). The mixture was stirred at room temperature for 2 minutes,treated with potassium cyanide (0.1 g.) in water 10 ml.), and pouredinto water (200 ml.). The precipitate was collected and stirred withmethanol, the insoluble portion being rejected. The residue fromevaporation of the methanol was purified by thin-layer chromatography onsilica gel, eluting with toluene/ethyl acetate and by crystallisationfrom hexane, affording 17u-n-octa-1',3'-diynyl-3-methoxy-oestra-l,3,5(10)-trien-17fl-ol, M.P. 74.5 C., [04 --40 (c. 1.1in CHCl 1512? 278 m (e, 1990), 287 m (0, 1870); A5,? 259 my (6, 410),219.5 m (e, 8900) The compound had high oestrogenic and claudogenicpotency.

EXAMPLE 8 17a-hexa-1',3-diynyl-3-methoxy-oestra- 1,3,5 10)-trien-17p-olA213, 278 my (6, 2070), 287 mp. (e, 1960); xii? 219 m 1 (6, 10,000), 258m (e, 034); .335; 3000, 2240, 1009, 1947 cmr CS2 1250, 1238, 1042 cm.

finax.

The compound had very high oestrogenic and claudogenie acivity.

8 EXAMPLE 9 17a-hepta- 1 ,3 -diynyl-3 -methoxy-oestra- 1,3 ,5 10 -trien-17/3-01 OH Mei max. 7 max.

The compound had very high oestrogenic and claudogenie activity.

EXAMPLE 1O 17oc-hCX21-1',3 -diynyl-3, 17 fl-dimethoxy-oestra- 1,3,5( 10) triene OMe But-l-yne was reacted with17a-br0moethynyl-3,17,8-dimethoxy-oestra-1,3,5(10)-triene by the methodof Example 2, alfording17vc-hexa-1,3'-diynyl-3,17,6-dimethoxyoestra-1,3,5(10)-triene, M.P. 805C., [121 -53 (c. 0.22 in dioxan); N.M.R. 6.231- (17,B-OMe), 6.601- (3-OMe), 9.1367 (18 Me);

133? 278 m (0, 2045 287 m (e, 1925 EXAMPLE 11 max.

17a-n-hepta-1,3-diynyl-3,17/3-dimethoxy-oestra-1,3,5 (10) -triene 0M0 Me1 n-Pent-l-yne was reacted with17ot-bromoethynyl-3,17fldimethoxy-oestra-1,3,5(10)-triene by the methodof Example 2, affording17a-n-hepta-1',3'-diynyl-3,l7fi-dimethoxy-oestra- 1,3 ,5 10) -triene,

A232? 278 m (e, 2030), 287 III/.L (e, 1915); 13 3 2243, 1010, 1498 cmf95,2; 1097 cmf 9 EXAMPLE 12 170L-I1-0Cta-1',3 -diynyl-3,17B-dimethoxy-oestra-1,3,5 10) triene OMe lPropyne (3 g.) inN,N-dimethyl-formamide (25 ml.) was added to a stirred mixture ofcuprous chloride (0.2 g.), hydroxylamine hydrochloride (0.36 g. aqueousethylamine (5.2 ml.: 70% N,N-dimethy1formamide (40 ml.) and methanol (25ml.), under nitrogen, and the mixture was stirred for a further 5minutes. 17a-bromoethynyl-3- methoxy-oestra-2,5()-dien-17/3-ol (2.0 g.)(US. Patent 3,072,646) in N,N-dimethyl-formamide ml.) was added and themixture was stirred for a further 1 hour, and poured into water. Thesteroidal product was extracted with ether, the ethereal solution wasdried over sodium sulphate and the solvent was removed at reducedpressure. The residue, in methanol (75 ml.) was treated with 3 Nhydrochloric acid (30 ml.) at 60 C. for 15 minutes. The methanolicsolution was poured into water and the steroidal product was extractedwith ether. The ethereal solution was Washed with sodium bicarbonatesolution and with water, dried over sodium sulphate and the solvent wasremoved at reduced pressure. The residue, purified by chromatography onalumina, eluting with toluene and by crystallisation from ether,afforded 17a-penta-1',3'-diynyl- 19-norandrost-4-en-l7p-ol-3-one, M.P.112 (3., [061113 -94 (0. 1.28 in dioxan);

But l yne was reacted with 170: bromoethynyl 3 methoxy oestra 2,5(10)dien 17p 01 by the method of Example 13. Purification by chromatographyon alumina, eluting with toluene, and by crystallisation from aqueousmethanol afforded a hexa 1,3- diynyl 19 norandrost' 4 en 17/3 ol 3 one,M.P. 163 C.; [(1113 101 (c. 0.6 in dioxan);

xEtOH 240 m (e, 17,300), g? 3605, 2235, 1670, 1620 max. X. cmf .33;1255, 1048 6111- The compound had high progestational activity.

EXAMPLE 15 17a-n-hepta-l,3-diynyl-19-norandrost-4-en- 17fl-ol-3-one OLVPent 1 yne was reacted with 17a-bromoethynyl-3- methoxy oestra 2,5(10)dien 17B 01 by the method of Example 13. Purification by chromatographyon alumina; eluting with toluene, and by crystallisation frommethanol/methylene chloride alforded 17a nhepta 1',3' diynyl 19norandrost 4 en 17B- 01 3 -oue. M.P. 199.5 C., [01],; --95 (c. 1.0 indioxan);

A 240 m (6, 17,100); 7:131: 3698, 1077, 1622 carmax.

The compound had high progestational activity.

EXAMPLE 16 17a-n-octa-1,3-diynyl-19-norandrost-4-en-175- ol-3-one n Hex1 yne was reacted with 17oz bromoethynyl 3 methoxy oestra 2,5(10) dien17,3 01 by the method of Example 13. Purification by chromatography onalumina, eluting with toluene, and by crystallisation frommethanol/methylene chloride afforded 17oz n octa 1,3 diynyl 19norandrost 4 enol 3 one, M.P. 228.5 C., [111 81 (c. 1.2 in CHCI EXAMPLE17 17a octa 1',3,5 triynyl 3,175 dimethoxyoestra-1,3,5( 10) -triene OMeMeO-

methoxy oestra 1,3,5(10) triene (4.0 g.) in N,N- dirnethyl formamide (30ml.) was added, and stirring was continued for a further 1% hours.Potassium cyanide (0.4 g.) in water (30 ml.) was added, followed by morewater (150 ml.). The mixture was extracted with ether, the etherealsolution was washed with water, dried over sodium sulphate andevaporated at reduced pressure. The residue, purified by chromatographyon alumina, eluting with petroleum ether (B.P. 6080 C.), aiforded17aocta 1,3',5' triynyl 3,17)? dimethoxyoestra-l,3, (10)-triene, [M 88(c. 0.99 in dioxan);

x523 207 m (6, 121,000), 216 m). (6, 125,000); 279 11 (e, 2130), 233 m(e, 2030 312 III/J (e, 167); 751;: 2130, 1609, 1574, 1498, 1337, 1256,1238, 1100, 1049 EXAMPLE 18 17a-hepta-1,3,5'-triynyl-3-methoxy-oestra-1,3,5()-trien-17,8-ol

Me O

A233? 277 m E, 2240 286 m 2200 303 m (e, 235),- .31 3590, 2210 cm.-1256,1236, 1036 cut- EXAMPLE 19 17a-octa-1',3 '-diynyl-oestral ,3,5(10)-triene-3,17B-diol 17a-ethynyl-oestra-1,3,5(10)-trien-3,175-diol(2.80 g.) in N,N-dimethyl-formamide (60 ml.) was added to a stirredmixture of cuprous chloride (0.20 g.), hydroxylamine hydrochloride (0.36g.), methanol (25 ml.) N,N-dimethyl-formamide (40 ml.) and aqueousethylamine (5.2 ml.: 70%) under nitrogen at 0 C. After 1 hourl-bromo-n-hex-l-yne (2.25 g.) in N,N-dimethyl-formamide (20 ml.) wasadded dropwise during 45 minutes. More hydroxylamine hydrochloride (0.10g.) was added to discharge a blue coloration which appeared at the endof this time. The mixture was stirred for 1% hours at room temperature,and treated with potassium cyanide (0.53 g.) in water (6 ml.). Morewater was added and the steroidal product was isolated by extractionwith ether. Purification by crystallisation from ether gave 170a octa1',3'-diylnyl-oestra-1,3,5(10)-trien-3,17,8-diol, M.P. 205 C., [a] 6l.5(c. 0.67 in dioxan), A 282 m (6, 2100), A 220 m (e, 7830), 259 In (6,617), 287 III/.0 (e, 1890).

12 EXAMPLE 20 17,8 hydroxy-6u-methyl-17tx-octa-1,3-diynyl-androst-4-en-3-one OH Me a ethy'nyl-17fl-hydroxy-6a-methyl-androst-4-en-3- oneAckroyd, Adams, Ellis, Petrow and Stuart-Webb, J. Chem. Soc., 1957, 4099(3.07 g.) in N,N-dimethylformamide (60 ml.) was added to a stirredmixture of cuprous chloride (0.20 g.), hydroxylamine hydrochloride (0.36g.), methanol (25 ml.), N,N-dimethyl-formamide (40 ml.) and aqueousethylamine (5.2 ml. 70%) under nitrogen at 0 C. After 1% hours,l-bromo-n-hex-lyne (2.25 g.) in N,N-dimethyl-formamide (20 ml.) wasadded dropwise during 20 minutes. More hydroxylamine hydrochloride (0.36g.) was added to discharge a blue coloration which appeared towards theend of this time. The mixture was stirred for 1% hours, at 0 C. andtreated with potassium cyanide (0.53 g.) in water (6 ml.). More waterwas added and the steroidal product was isolated by extraction withether. Purification by crystallisation from acetone/hexane andether/hexane gave hydroxy 6a methyl-17a-octa-1',3-diynyl-androst-4-en-3-one, M.P. 123 C., [0;]; -26 (c. 0.79 in dioxan),

EXAMPLE 21 3-diethylaminoethoxy-17a-octa-1',3-diynyl-oestra-1,3,5(10)-trien-17 8-ol EtgNCHiCHiO 3 diethylaminoethoxy 1712-ethynyl-oestra-1,3,5(10- trien-l7fl-ol (2.80 g.) (D. D. Evans, D. E.Evans, G. S. Lewis, P. J. Palmer and D. J. Weyell, J. Pharm. Pharmacol,1964, 16, 717) in N,N-dimethyl-formamide (40 ml.) was added to a stirredmixture of cuprous chloride (0.14 g.), hydroxylamine hydrochloride (0.24g.), methanol (17 ml.), N,N-dimethyltormamide (30 ml.) and aqueousethylamine (3.8 ml. 70%) under nitrogen at 0 C. After 1 hour1-bromo-n-hex-1-yne (1.75 g.) in N,N-dimethylforn1amide (20 ml.), wasadded dropwise, during 45 minutes. More hydroxylamine hydrochloride (0.1g.) was added to discharge a blue coloration which appeared towards theend of this time. The mixture was stirred for 1% hours at roomtemperature. Potassium cyanide (0.5 g.) in water (6 ml.) was added andthe mixture was poured into water. The steroidal product was isolated byextraction with ether and treated in anhydrous ether with a saturatedethereal solution of maleic acid. Absolute ethanol was added toredissolve the precipitated oil, and the mixture was allowed to stand at0 C. The maleic acid salt of 3-diethylaminoethoxy 170a octa-1',3' diynyloestra-1,3,5- (10)-trien-17,8-ol separated as needles, M.P. 77.5 C., [M31 (0. 0.68 in ethanol).

The above salt (0.3 g.), suspended in ether (50 ml.) was shaken at roomtemperature for 10 minutes with 1 N sodium hydroxide solution (50 ml.).The ether layer was separated, washed with water, dried (Na SO and freedfrom solvent at reduced pressure, aflording amorphous 3diethylaminoethoxy-17ot-octa-1,3-diynyloestra-1,3,5(10)-trien-17;3-ol.

V22; 3505, 224.0, 1609 cm.

EXAMPLE 22 Rae-171x- (hexa-1',3'-diynyl) 3methoxy1 8-methyloestra- 1,3,510 -trien- 175-01 on e o-050.101

Rae-

MeO-

A mixture of cuprous chloride (0.25 g.), hydroxylamine hydrochloride(0.5 g.), dimethylformamide (50 ml.), methanol (31.5 ml.) and 70%aqueous ethylamine (6.5 ml.) was stirred under nitrogen and a solutionof raw 17a ethynyl'3-methoxy-18-methyloestra-1,3,5(10)- trien-17,B-ol(Chem. 'Pharm. Bull. Japan, 1965, 13, 1293) (3.5 g.) indimethylformamide (50 ml.) was added. After stirring for 1 hour at roomtemperature the mixture was cooled in ice and a solution ofl-bromo-but-l-yne (prepared by reaction of but-l-yne with aqueouspotassium hypobromite) (2 g.) in dimethylformamide (40 ml.) was addedover 1 hour. The mixture was allowed to warm to room temperature over1.5 hour and a solution of potassium cyanide (0.75 g.) in water (10 ml.)was added. The precipitated material was extracted into ether, theextract was washed with water, dried (Na SO and evaporated. The residualgum was purified by preperative thin-layer chromatography on silica gelimpregnated with silver nitrate (12 plates, 20 x 40 x 0.1 cm., developedin benzene:ethyl acetate-1:1) and by chromatography on a column ofalumina (eluted with ether). Rac-l7u-(hexa- 1,3' diynyl) 3methoxy-18-methyloestra-1,3,5(10)- trien-17B-o1 was obtained as a paleyellow gum having A232? 278 (6 2,100 and 286.5 111,. (6 1,000 and 1 33600, 2210, 1610 and 1500 cm? EXAMPLE 2317ot-phenylbutadiynyl-androst-5-ene-3p,17fi-diol OH Me W (1) 170aethynyl-androst-ene-3B,17fi-diol (2.00 g.) in N,N-dimethylformamide (60ml.) was added to a stirred mixture of cuprous chloride (0.40 g.),hydroxylamine hydrochloride (0.72 g.), methanol (52 ml.), N,N-dimethylformamide (80 ml.) and aqueous ethylamine (10.4 ml.: 70%) undernitrogen at room temperature. After 1 hour, bromoethynyl benzene (Wilsonand Wenzke, J. Amer. Chem. Soc., 1934, 56, 2025) (3.3 g.) inN,N-dimethylformamide (5 ml.) was added dropwise and the mixture wasstirred for 1 hour at room temperature. Potassium cyanide (0.8 g.) inwater ml.) was added, followed by more water (100 ml.). The precipitatewas collected and purified by thin-layer chromatography on silica-gel.Elution with toluene-ethyl acetate, and crystallisation of the productfrom aqueous methanol, gave 17m phenylbutadiynylandrost-5-ene-3B,17fl-diol, M.P. 253 C., -189 (c. 0.79 in dioxan), A 225m (e 56346), 234 mu (e 3710), 246 Ill .1. (e 8620), 259 m (E 19860), 274m (6 31630), 291m (e 26490).

(2) Lithium (0.51 g.) and ferric nitrate (trace) were added to anhydrousliquid ammonia (1.5 l.) and the mixture was stirred under reflux untilthe blue colour disappeared. 3B,17B bis(tetrahydro 2pyranyloxy)-17aethynyLandrost-S-ene (14.7 g.) (S. P. Barton, D. Burn, G.Cooley, B. Ellis and V. Petrow, J. Chem. Soc., 1959, 1957) in anhydroustetrahydrofuran (510 ml.) was added and the mixture was stirred underreflux for 75 minutes. A slow stream of gaseous bromo-trifluoromethanewas then passed into the mixture for 2 hours. The ammonia was allowed toevaporate, ammonium chloride and water were added, and the steroidalproduct was isolated by extraction with ether. It was treated inmethanol 1.5 l.) with 4 N hydrochloric acid (10 ml.) for 1 hour at roomtemperature. The solution was poured into water and the precipitatecrystallised from aqueous methanol, affording17a-bromoethynyl-androst-5-ene-3B,l7p-diol, M.P. 209 C., -97 (c. 0.96 indioxan).

Ethynyl-benzene (3.5 ml.) was added to a stirred mixture of cuprouschloride (0.33 g.), hydroxylamine hydrochloride (0.59 g.), methanol (42ml.), N,N-dimethy1- formamide (65 ml.) and aqueous ethylamine (8.5 ml.:70%), under nitrogen at room temperature. After 10 minutes, the mixturewas cooled to 0 C. and 170t-bI'OII10- ethynyl-androst-5-ene-3B,17,8-diol(6.34 g.) in N,N-dimethylformamide (65 ml.) was added dropwise during 20minutes. The mixture was stirred at room temperature for 1% hours.Potassium cyanide (0.65 g.) in water (65 ml.) was added, and the mixturepoured into water. The precipitate was crystallised from aqueousmethanol, affording 170a phenylbutadiynyl androst 5 -ene-3 8,l7B-diol,identical with the sample prepared as described above.

The steroidal starting material used in Examples 1, 5, 7, 8, 9 and 18was prepared as follows:

Liquid ammonia (100 ml.) containing lithium (0.07 g.) and a trace offerric nitrate was stirred under reflux until the blue colour haddisappeared. 17 3-tetrahydropyranyl ether of17u-ethynyl-3-methoxyoestra-1,3,5(10)- trien-17fi-o1 (Cross, Harrison,Kincl, Farkas, Kraay and Dorfman, Steroids, 1964, 4, 429) (1.4 g.) inanhydrous tetrahydrofuran (70 ml.) was added, and the mixture stirredunder reflux for 2 hours. Bromotrifluoromethane (20 g.) was slowlypassed into the mixture during 3 hours. The ammonia was allowed toevaporate, ammonium chloride (5 g.) was added, followed by water (300ml.), and the product was isolated with ether. Its solution in ethanol(30 ml.), water (3 ml.) and acetic acid (5 ml.) was refluxed for 4hours. The product obtained by addition of water and extraction wasether was purified from aqueous methanol to give 17a-bromoethynyl-3-methoxyoestra-1,3,5(10)-trien-17,B-ol, M.P. 168-170 C., [04],; -15" (indioxan).

The steroidal starting material used in Examples 2, 3, 4, 10, 11, 12 and17 was prepared as follows:

Liquid ammonia (100 ml.) containing lithium (0.05 g.) and a trace offerric nitrate was stirred under reflux until the blue colour haddisappeared. 17a-ethynyl-3,17fldimethoxyoestra-1,3,5(10)-triene (GermanPatent 1,062,- 698) (1.0 g.) in anhydrous tetrahydrofuran (50 ml.) wasadded, and the mixture stirred under reflux for 2 /2 hours.Bromotrifluoromethane (14 g.) was passed in slowly while the mixture wasstirred for a further 2 /2 hours. The ammonia was allowed to evaporate,ammonium chloride (3 g.) was added, followed by water (200 ml.). Thesteroidal precipitate was purified from methanol to give 17abromoethynyl 3,173 dimethoxyoestra- 1,3,5(10) triene, M.P. 131132 C.,[ab -34 (in chloroform) We claim:

1. A process for the preparation of substituted 17abuta-1',3-diynyl-17flhydroxy(l7fl-alkoxy)-steroids having the partial formula OR o-cEo-oEc-Rwhere R is H or an alkyl group containing not more than 5 carbon atoms,and R is an alkyl, hydroxyalkyl or alkenyl group containing not morethan 5 carbon atoms, or an alkylnyl group containing not more than 7carbon atoms, or an aryl group containing not more than 9 carbon atoms,which process comprises treating an ethynyl compound -CECH with acuprous salt and a bromoethynyl compound R'CECBr where one of R" and Rrepresents a steroidal moiety with the ethynyl or bromoethynyl groupattached at C and the other of R" and R represents an alkyl,hydroxyalkyl or alkenyl group containing not more than 5 carbon atoms,or an alkynyl group containing not more than 7 carbon atoms, or an arylgroup containing not more than 9 carbon atoms.

2. A process as claimed in claim 1 wherein a catalytic quantity ofcuprous chloride is employed as cuprous salt.

3. A process as claimed in claim 1 wherein of the two reagents R"CECHand R"CECBr the non-steroidal reagent is present in excess and thereaction is carried out in the presence of a base and of a reducingagent which will maintain the copper in the cuprous state.

4. A process as claimed in claim 3 wherein the base is ethylamine.

5. A process as claimed in claim 3 wherein the reduc ing agent is a saltof hydroxylamine.

6. A process as claimed in claim 1 wherein the reaction is carried outunder an inert atmosphere at temperatures between l C. and 40 C.

7. A process as claimed in claim 1 wherein the reaction is carried outin polar organic solvents.

8. A process as claimed in claim 7 wherein the polar organic solventscomprise mixtures consisting of an alcohol and N,N-dimethyl-formamidecontaining some water.

9. A process as claimed in claim 1 wherein the reaction is completed inup to 2 hours and potassium cyanide is then added to destroy anyresidual acetylenic cuprous compound.

10. A steroid compound selected from the group consisting ofl7a-hydroxyalkyl-, 17u-alkenyl-, Nor-alkynyland17a-aryl-buta-1,3'-diynyl-17fi hydroxy(17p-alkoxy)- steroids of the'androstane and oestrane series having at C-17 the structure ORJ--oEo-oEc-R where R is H or an alkyl group containing not more than 5carbon atoms and R is a hydroxyalkyl or alkenyl group containing notmore than 5 carbon atoms or an alkynyl group containing not more than 7carbon atoms or an aryl group containing not more than 9 carbon atoms.

11. A compound according to claim 10 consisting of 17u-(5-hydroxy-penta1,3'-diynyl) 3,17,8-dimethoxyoestra-1,3,5(10)-triene.

12. A compound according to claim 10 consisting of17a-(4'-phenyl-buta-1,3' diynyl) 3,175 dimethoxyoestra-1,3,5(10)-triene.

13. A compound according to claim 10 consisting of hex 5'en-1',3-diynyl-3-methoxyoestra-1,3,5(10)- trien- -01.

14. A compound according to claim 10 consisting of 17a octa 1,3,5'triynyl 3,l7fi-dimethoxyoestra-1,3,5 (10)-triene.

15. A compound according to claim 10 consisting of 17a-hepta 1,3,5triynyl 3-methoxy-oestra-1,3,5(10)- trien-17B-ol.

16. A compound according to claim 10 consisting of17a-phenylbutadiynyl-androst-5-ene-35,17,8-diol.

17. 17a-n-octa-1',3-diynyl-androst-5-en-3,l7B-diol.

18. 17a octa 1',3' diynyl-oestra-1,3,5(10)-triene- 3,17,3-diol.

19. 17,8 hydroxy 6a methyl 17a-octa-1,3'-diyny1- andrcst-4-en-3-one.

20. 3 diethylaminoethoxy 17a octa 1',3'diynyloestra-1,3,5 10-trien-17fi-ol.

21. Rac 170a (hexa l,3-diynyl)-3-methoxy-18- rnethyloestra-1,3,5( 10)-trien-17fl-ol.

22. A compound of the formula:

IAQ

wherein: R is hydroxyalkyl of up to 5 carbon atoms, alkenyl of up to 5carbon atoms, alkynyl of up to 7 carbon atoms, or aryl of up to 9 carbonatoms; R is hydrogen or alkyl of up to 5 carbon atoms; R is hydrogen,alkyl of up to 5 carbon atoms, or dialkylaminoalkylin which the alkylgroups contain up to 5 carbon atoms; and R is hydrogen or methyl.

References Cited UNITED STATES PATENTS 3,164,617 1/1965 Feather et a1.260397.4

FOREIGN PATENTS 1,108,758 4/1968 Great Britain.

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

